Stabilized Compositions Comprising a Therapeutically Active Agent, and an Oxidizing Preservative

ABSTRACT

Citric acid and conjugate bases thereof are useful for stabilizing stabilized chlorine dioxide in the presence of therapeutically active agents and excipients in a composition. Ophthalmic compositions and methods related thereto are also disclosed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a national stage application under 35 U.S.C. § 371 of PCTapplication PCT/US 2005/018026, filed on May 19, 2005, which claims thebenefit of Nonprovisional application Ser. No. 10/865,639, filed on Jun.9, 2004.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions. Inparticular, the present invention relates to ophthalmic compositionscontaining an active drug and the use of stabilized chlorine dioxide asa preservative in these compositions.

BACKGROUND OF THE INVENTION Description of Related Art

Preservatives are used in multi-use ophthalmic formulations to preventmicrobial contamination of the composition after the packaging has beenopened. A number of preservatives have been used including quaternaryammonium salts such as benzalkonium chloride; mercury compounds such asphenylmercuric acetate and thimerosal; alcohols such as chlorobutanoland benzyl alcohol; and others. Recently, stabilized chlorine dioxidehas also been disclosed as being useful as a preservative in ophthalmiccompositions, see for example, U.S. Pat. No. 5,736,165; U.S. Pat. No.5,424,078; and WO 9602264A2; all of which are expressly incorporatedherein by reference.

At least one commercial ophthalmic product, Alphagan P®, marketed byAllergan, Inc., the assignee of the present patent document usesstabilized chlorine dioxide as a preservative. The active agent ofAlphagan P® is brimonidine, an alpha 2-adrenoceptor agonist, and theproduct is used for the treatment of glaucoma and other conditionsassociated with elevated intraocular pressure.

SUMMARY OF THE INVENTION

One embodiment comprises an ophthalmic composition comprising aneffective amount of a therapeutically active agent, stabilized chlorinedioxide, and citric acid and/or conjugate bases thereof.

A method of stabilizing incompatible components of a compositioncomprising adding an effective amount of citric acid and/or conjugatebases thereof, wherein said incompatible components comprise stabilizedchlorine dioxide and a second component, is also disclosed herein.

Another embodiment comprises a method of preserving an ophthalmiccomposition comprising providing an effective amount of citric acidand/or conjugate bases thereof and stabilized chlorine dioxide to saidcomposition.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 shows the effect of citrate on bimatoprost stability in thecomposition of Table 4 at 50° C.

FIG. 2 shows the effect of citrate on Purite® stability in thecomposition of Table 4 at 50° C.

DETAILED DESCRIPTION OF THE INVENTION

We have found many therapeutically active agents and some othercomponents of many ophthalmic compositions are incompatible withstabilized chlorine dioxide, which is a useful preservative forophthalmic compositions. Particularly, stabilized chlorine dioxide andtherapeutically active agents or other components of an ophthalmicformulation are unstable in one another's presence. In other words, ifstabilized chlorine dioxide is in a composition with certaintherapeutically active agents, either the stabilized chlorine dioxide,or the therapeutically active agent, or both, are unstable. Similarly,if stabilized chlorine dioxide is in a composition with certain otherexcipients, either the stabilized chlorine dioxide, or the otherexcipient, or both, are unstable. Surprisingly, citric acid and/orconjugate bases thereof have been discovered to improve the stability ofthese combinations.

As used herein, the term “therapeutically active agent” is understood inthe broadest sense generally accepted in the art to be a compound orcompounds which are used to treat or prevent any disease or undesirablecondition which afflicts an animal.

The term “stabilized chlorine dioxide” is well known in the industry andby those skilled in the art. The term “stabilized chlorine dioxide” asused herein means, for example, one or more chlorine dioxide-containingcomplexes disclosed in U.S. Pat. Nos. 4,696,811 and 4,689,215, which areincorporated herein by reference. Chlorites include metal chloritesalts, particularly alkali metal chlorites. A specific example of achlorite salt which is useful as a chlorine dioxide precursor is sodiumchlorite. Among the preferred stabilized chlorine dioxide complexes arecarbonate and bicarbonate complexes. The exact chemical composition ofmany of these stabilized chlorine dioxide precursors is not completelyunderstood. The manufacture or production of certain chlorine dioxideprecursors is described in McNicholas U.S. Pat. No. 3,278,447, which ishereby incorporated in its entirety by reference herein. A commerciallyavailable stabilized chlorine dioxide which can be utilized in thecompositions disclosed herein is the proprietary stabilized chlorinedioxide of BioCide International, Inc. of Norman, Okla., sold under thetrademark Purite®. Other suitable stabilized chlorine dioxide productsinclude that sold under the trademark Dura Klor® by Rio Linda ChemicalCompany, Inc., and that sold under the trademark Antheium Dioxide® byInternational Dioxide, Inc. The amount of stabilized chlorine dioxideused depends upon the therapeutically active agent, other excipients,and other aspects of the formulation process. Such a determination canreadily be made by a person of ordinary skill in the art, without undueexperimentation. While the amount of stabilized chlorine dioxide mayvary widely, a concentration between 30 ppm and 500 ppm is useful inmany compositions. In other compositions, from 50 ppm and 150 ppmstabilized chlorine dioxide is used.

The term “citric acid and/or conjugate bases thereof” refers to citricacid and its monovalent (-1), divalent (-2), and trivalent (-3) salts inany combination. Thus, any one of these species and any combinationthereof is considered to be within the meaning of the phrase “citricacid and/or conjugate bases thereof”. The concentration of citric acidin the compositions disclosed herein may vary. In some compositions, theconcentration of citric acid and/or conjugate bases thereof is from0.001% to 0.10%. In other compositions, the concentration of citric acidand/or conjugate bases thereof is about 0.02%. Unless a specific amountof a specific form is indicated, the concentration of citric acid and/orconjugate bases thereof is determined as if all citric acid and citratespecies were citric acid.

U.S. Pat. No. 5,246,662 teaches that transition metals are capable ofcatalyzing the conversion of stabilized chlorine dioxide to the activeform. Thus, while not intending to be limited or bound in any way bytheory as to the scope of the present invention, it is believed thattrace transition metals help to accelerate the formation of activechlorine dioxide, which in turn oxidizes the therapeutically activeagent or an excipient. Thus, it is believed that citric acid acts as achelating agent to bind up these trace metals, stabilizing theincompatible components in each others' presence. While the trace metalsare not deliberately added, it is believed that sufficient quantities ofthese metals are present in common ophthalmic excipients to effect thefreeing of chlorine dioxide. Furthermore, while not intending to bebound in any way by theory, it is believed that the citric acid enhancesthe preservative effectiveness because binding the metal deprivesmicrobial contaminants of nutrients, thus inhibiting their growth,and/or helping to kill the pathogen.

While not intending to be bound in any way by theory, it is believedthat polyanions such as carboxymethylcellulose (CMC) have a sufficientquantity of transition metal impurities to overcome the chelatingproperties of these compounds, such that they do not stabilize theincompatible components, but can actually destabilize them. It isbelieved that this is because polymeric materials are much moredifficult to purify than small molecules, due to the fact that thesematerials generally constitute a mixture, and are not a pure, singlecompound. It is believed that this is the reason thatcarboxymethylcellulose was observed to destabilize certain incompatiblecomponents. By contrast citric acid is believed to be sufficiently pureto stabilize the incompatible components contemplated herein.

While not intending to be bound in any way by theory, it is alsobelieved that many chelating agents have oxidizable groups which makethem unsuitable for stabilizing chlorine dioxide. For example, amineswith amine functional groups such as EDTA and ethylene diamine areoxidized by the stabilized chlorine dioxide, and are thus not suitablechelating agents for the purposes disclosed herein.

While not intending to be bound in any way by theory, other potentialchelating agents such as lactate, pyruvate, and oxalate, are believed toeither be too weak as metal chelating agents to be effective, orsusceptible to oxidation, or both, such that they do not appear tostabilize the incompatible components of a composition.

In one embodiment, the therapeutically active agent of the compositionsdisclosed herein is bimatoprost which is a prostamide compound. Whilenot intending to be bound in any way by theory, it is generally believedin the art that oxidation reactions are generally nonselectivereactions, the fact that stabilized chlorine dioxide destabilizesbimatoprost suggests that a broad variety of compounds will be oxidizedby chlorine dioxide. Furthermore, chlorine dioxide is a strong oxidant(as evidenced by the fact that we are using “stabilized” chorinedioxide), and would thus be even less selective than a “normal” oxidant.For comparison, the standard reduction potential of chlorine dioxide toClO₂ ⁻ is 1.07 V, whereas the standard reduction potential ofpermanganate to manganese dioxide is 0.6 V [Schriver, Atkins, Langford,Inorganic Chemistry, New York: W.H. Freeman and Company, 1990, pp. 649and 654]. Permanganate has been used as a reagent for many oxidations inorganic chemistry including the oxidative cleavage of alkenes to ketonesor carboxylic acids, the oxidative cleavage of ketones to carboxylicacids, the oxidation of alcohols or aldehydes to carboxylic acids, andvarious oxidations of amine and sulfur containing functional groups.Thus, while not intending to be bound in any way by theory, chlorinedioxide, being a stronger oxidizing agent than permanganate, is expectedto oxidize many functional groups.

In one embodiment, the therapeutically active agent comprises acarboxylic acid, a carboxylic acid ester, or a carboxylic acid amide. Inanother embodiment, the therapeutically active agent is a prostaglandinor prostamide such as bimatoprost, latanoprost, travoprost, unoprostoneisopropyl, and the like, which have carboxylic acid, ester, or amidegroups. In another embodiment, the therapeutically active agentcomprises a sulfur atom. Other functional groups that may be susceptibleto stabilized chlorine dioxide are amines, phenols, alcohols, aromaticamino acids, non-conjugated double bonds, and similar groups. While notintending to be limiting, or to be bound by theory, non-activeexcipients comprising one or more of the aforementioned functionalgroups should be stabilized by citric acid such that they can be usedwith stabilized chlorine dioxide.

As is known in the art, buffers are commonly used to adjust the pH to adesirable range for ophthalmic use. Generally, a pH of around 6-8 isdesired, however, this may need to be adjusted due to considerationssuch as the stability or solubility of the therapeutically active agentor other excipients. Many buffers including salts of inorganic acidssuch as phosphate, borate, and sulfate are known. Although any buffermay be used in the compositions disclosed herein, in certain situationsit is particularly useful to use a borate/boric acid buffer in thecompositions disclosed herein. The term “borate/boric acid buffer”refers to any combination of boric acid and one or more of the conjugatebases such that the pH is adjusted to the desired range. While notintending to limit the scope of the invention in any way, or be bound inany way by theory, it is believed that the borate/boric acid buffer mayboost the antimicrobial properties of stabilized chlorine dioxide.

In another embodiment, the therapeutically active agent is aprostaglandin or a prostamide. In another embodiment, thetherapeutically active agent is bimatoprost. One composition comprisesfrom 0.01% to 0.10% bimatoprost. In another embodiment, theconcentration of bimatoprost is about 0.03%.

Another commonly used excipient in ophthalmic compositions is aviscosity-enhancing, or a thickening agent. Thickening agents are usedfor a variety of reasons, ranging from improving the form of theformulation for convenient administration to improving the contact withthe eye to improve bioavailability. The viscosity-enhancing agent maycomprise a polymer containing hydrophilic groups such asmonosaccharides, polysaccharides, ethylene oxide groups, hydroxylgroups, carboxylic acids or other charged functional groups. While notintending to limit the scope of the invention, some examples of usefulviscosity-enhancing agents are sodium carboxymethylcellulose,hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, andpolyethylene glycol.

Another composition comprises 0.03% bimatoprost, 0.39% sodium chloride,0.6% boric acid, 0.045% sodium borate decahydrate, 0.014% citric acidmonohydrate, 0.5% carboxymethylcellulose, and 0.005% Purite® (stabilizedchlorine dioxide), wherein the pH is adjusted to 7.3 by the addition ofhydrochloric acid (HCl) or sodium hydroxide (NaOH).

In ophthalmic solutions, tonicity agents often are used to adjust thecomposition of the formulation to the desired isotonic range. Tonicityagents are well known in the art and some examples include glycerin,mannitol, sorbitol, sodium chloride, and other electrolytes.

The best mode of making and using the present invention are described inthe following examples. These examples are given only to providedirection and guidance in how to make and use the invention, and are notintended to limit the scope of the invention in any way.

EXAMPLE 1

The following example is typical of the instability of various commonophthalmic excipients in the presence of stabilized chlorine dioxide.Each of the excipients was added, in the amounts shown, to a proprietarycomposition comprising brimonidine as a therapeutically active agent.The results, presented in Table 1, show that none of the excipientsappear to stabilize the chlorine dioxide. In particular, EDTA andethylene diamine, which are known chelating agents, do not stabilize thechlorine dioxide. Also of note is that some of the other compounds thatmight be viewed as chelating agents, such as oxalate or pyruvate, aresimilarly ineffective.

TABLE 1 Effect of Chelating Agents on Stability of Chlorine DioxideStabilized Chlorine Dioxide Concentration (ppm) Ingredient (ppm) pH 0Days 7 Days 14 Days None (control) 7.3 42 41 38 Sodium Formate (100) 7.342 40 36 Sodium Lactate (100) 7.3 45 40 37 Sodium Pyruvate (100) 7.3 4115 0 Sodium Dihydroxyfurmarate (100) 7.1 37 13 0 Sodium Oxalate (100)7.3 39 38 35 Ethylene diamine (100) 7.2 42 37 29 EDTA (100) 7.2 44 2 0Sodium Oxalate (100) + Fe(III) (1) 7.3 43 38 39 Ethylene oxide (100) 7.343 40 35 Acetone (100) 7.3 43 38 35 Glucose (100) 7.3 43 41 34

EXAMPLE 2

Compositions A, B, and C were prepared according to Table 2. Allcompositions were prepared in a similar manner. A composition ismanufactured on a volume basis at ambient temperatures from twoprincipal parts designated I and II. Each in-process part is preparedseparately and then combined. The resulting bulk composition is pHadjusted and then brought to volume for final mix.

Part I is manufactured in the main batch vessel. Water is charged to themain mixing vessel at 50% of the final batch volume. Mixing is initiatedat a specified speed using a Rotosolver mixer positioned off-center toproduce a strong vortex, and CMC is added directly into the vortex. Thesolution is mixed for a specified time until complete dissolution isachieved.

Part II is manufactured in a separate mixing vessel equipped with atop-entering variable-speed mixer and an appropriately sized impeller.Water is charged to the tank at 35% of the batch volume ad mixing isinitiated at a specified speed. The ingredients for Part II are added inthe following order: boric acid, sodium borate, sodium chloride,bimatoprost, and Purite®. Each ingredient is allowed to completelydissolve before the next ingredient is added.

With continued mixing in the main batch vessel, Part II isquantitatively transferred into Part I. The combined parts are mixed fora specified time to ensure homogeneity. The pH is measured and adjustedto pH 7.3 with NaOH and/or HCl. Water is added to final volume and thebulk solution is mixed until homogeneous. The osmolality of the finalsolution is about 290 mOsm/kg.

The samples were held at 50° C. for 13 weeks and the concentration ofbimatoprost was determined by high performance liquid chromatography.The concentration of Purite® was determined by titration and is reportedas potential chlorine dioxide (CDO) concentration in ppm. The Purite®analysis procedure is based on the reduction of chlorite ion by iodidein acidic medium. The liberated iodine is then back-titrated usingsodium thiosulfate to calculate the amount of sodium chlorite. Resultsare reported as potential chlorine dioxide rather than in terms ofsodium chlorite (or Purite®) because CDO is the active form of thepreservative

While not intending to limit the scope of the invention in any way, theresults, presented in Table 3, demonstrate that the addition of lowviscosity carboxymethylcellulose polymer (CMC), with or without NaCl,tends to destabilize both the bimatoprost and the Purite®.

TABLE 2 Base Composition Comprising Bimatoprost and Purite ®.Concentration (% w/w) Ingredient A B C Bimatoprost 0.03 0.03 0.03 Purite0.015 0.015 0.015 Boric Acid 0.60 0.60 0.60 Sodium Borate 0.045 0.0450.045 Sodium Chloride 0 0 0.39 Carboxymethylcellulose 0 0.50 0.50HCl/NaOH pH to 7.3 pH to 7.3 pH to 7.3 Purified Water q.s. 100% q.s.100% q.s. 100%

TABLE 3 Bimatoprost and Purite ® Content in Formulations of Table 2After 13 Weeks at 50° C. Bimatoprost, % of Purite ®, % of CompositionInitial Initial Borate Buffer (A) 91.0 100.5 Borate + CMC (B) 84.5 95.7Borate + CMC + NaCl (C) 82.2 96.0

EXAMPLE 3

Compositions D and E were prepared according to Table 4 by a proceduresimilar to that described in Example 2. Citric acid was added after thedissolution of sodium chloride and the pH was measured and adjusted topH 7.3 with NaOH and/or HCl before the addition of bimatoprost andPurite®. The samples were stored at 50° C. and the concentrations ofbimatoprost (FIG. 1) and Purite® (FIG. 2) were determined at 3, 6 and 10weeks. While not intending to limit the scope of the invention in anyway, FIGS. 1 and 2 demonstrate that citrate stabilizes both bimatoprostand Purite® in the composition.

TABLE 4 Composition of Bimatoprost With and Without Citric AcidConcentration (% w/w) Ingredient D E Bimatoprost 0.03 0.03 Purite ®0.005 0.005 Citric Acid 0.014 — Boric Acid 0.60 0.60 Sodium Borate 0.0450.045 Sodium Chloride 0.39 0.39 Carboxymethylcellulose 0.50 0.50HCl/NaOH pH to 7.3 pH to 7.3 Purified Water q.s. 100% q.s. 100%

EXAMPLE 4

A composition, prepared according to Table 5, was entirely manufacturedin a single batch vessel and was prepared as follows. The ingredientsare added into purified water with mixing in the following order: sodiumphosphate dibasic heptahydrate, citric acid monohydrate, sodiumchloride, bimatoprost, and Purite®. Each ingredient was allowed todissolve completely before the next ingredient was added. The pH wasthen measured and adjusted to 7.3, and purified water was added to bringthe composition to final volume. After storage for six months at 40° C.,99.7% of initial bimatoprost and 99.6% of initial Purite® remained inthe product. While not intending to limit the scope of the invention inany way, these data demonstrate that the citrate provides excellentstorage stability for bimatoprost and Purite®.

TABLE 5 Composition of Bimatoprost in Phosphate/Citrate BufferIngredient Concentration (% w/w) E Bimatoprost 0.03 Purite ® 0.01 SodiumPhosphate Dibasic 0.268 Citric Acid 0.014 Sodium Chloride 0.83 HCl/NaOHpH to 7.3 Purified Water q.s. 100%

EXAMPLE 5

A composition according to example 4 is administered topically once aday to the eyes of a patient suffering from glaucoma. Reduction of thepatient's intraocular pressure is observed shortly after administration,and continues for as long as the composition is administered.

1. An ophthalmic composition comprising an effective amount of atherapeutically active agent, stabilized chlorine dioxide, and citricacid and/or conjugate bases thereof.
 2. The composition of claim 1wherein said therapeutically active agent comprises a sulfur atom. 3.The composition of claim 1 wherein said therapeutically active agentcomprises a carboxylic acid, a carboxylic acid ester, or a carboxylicacid amide.
 4. The composition of claim 1 comprising a prostaglandin ora prostamide.
 5. The composition of claim 1 which comprises bimatoprost.6. The composition of claim 1 comprising a borate/boric acid buffer. 7.The composition of claim 1 comprising from 0.01% to 0.10% bimatoprost.8. The composition of claim 1 comprising from 0.001% to 0.10% citricacid and/or conjugate bases thereof.
 9. The composition of claim 7comprising about 0.02% citric acid and/or conjugate bases thereof. 10.The composition of claim 8 comprising 0.03% bimatoprost, 0.39% sodiumchloride, 0.6% boric acid, 0.045% sodium borate decahydrate, 0.014%citric acid monohydrate, 0.5% carboxymethylcellulose, and 0.005%stabilized chlorine dioxide, wherein the pH is adjusted to 7.3 by theaddition of hydrochloric acid or sodium hydroxide.
 11. A method ofstabilizing incompatible components of a composition comprising addingan effective amount of citric acid and/or conjugate bases thereof tosaid composition, wherein said incompatible components comprisestabilized chlorine dioxide and a second component.
 12. The method ofclaim 11 wherein said second component is a therapeutically activeagent.
 13. The method of claim 12 wherein said therapeutically activeagent is a prostaglandin or a prostamide.
 14. The method of claim 13wherein said therapeutically active agent is bimatoprost.
 15. The methodof claim 14 wherein bimatoprost has a concentration of about 0.03%. 16.A method of preserving an ophthalmic composition comprising providing aneffective amount of citric acid and/or conjugate bases thereof andstabilized chlorine dioxide to said composition.
 17. The composition ofclaim 8 comprising about 0.03% bimatoprost, about 0.27% sodium phosphatedibasic heptahydrate, about 0.014% citric acid monohydrate, about 0.83%sodium chloride, and about 0.01% Purite®, wherein the pH is adjusted to7.3 by the addition of hydrochloric acid and/or sodium hydroxide. 18.The composition of claim 8 consisting essentially of about 0.03%bimatoprost, about 0.27% sodium phosphate dibasic heptahydrate, about0.014% citric acid monohydrate, about 0.83% sodium chloride, and about0.01% Purite®, water, and a sufficient quantity of hydrochloric acidand/or sodium hydroxide to adjust the pH is adjusted to 7.3.
 19. Thecomposition of claim 8 consisting of about 0.03% bimatoprost, about0.27% sodium phosphate dibasic heptahydrate, about 0.014% citric acidmonohydrate, about 0.83% sodium chloride, and about 0.01% Purite®,water, and a sufficient quantity of hydrochloric acid and/or sodiumhydroxide to adjust the pH is adjusted to 7.3.
 20. The composition ofclaim 8 comprising from 30 ppm to 500 ppm Purite®.